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Seizure 20 (2011) 635–639

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A prospective study of levetiracetam efﬁcacy in epileptic syndromes with

continuous spikes-waves during slow sleep

a, b,c

Mary Atkins *, Marina Nikanorova

Danish Epilepsy Centre, Department of Neurophysiology, Kolonivej 1, 4293 Dianalund, Denmark

Danish Epilepsy Centre, Childrens Department, Dr. Sells Vej 23, 4293 Dianalund, Denmark

A R T I C L E I N F O A B S T R A C T

Article history: Purpose: To evaluate the add-on effect of levetiracetam (LEV) treatment on the EEG and clinical status of

Received 3 January 2011

children with continuous spikes-waves during slow sleep (CSWS).

Received in revised form 19 May 2011

Methods: 20 children with CSWS refractory to other conventional antiepileptic drugs (AEDs) received

Accepted 15 June 2011

LEV 45–50 mg/kg/day as add-on treatment, and were prospectively followed for a minimum period of 18

months. The patient population comprised seven cryptogenic, seven symptomatic and six idiopathic

Keywords:

cases (atypical benign partial epilepsy, aBECTs). The electrographic evaluation included 24 h EEG

Epilepsy

recordings taken every six months (minimum of three per child). Electrographically children were

Continuous spike-waves

categorised as responders, partial responders or non-responders by comparing changes in the spike

Slow wave sleep

Levetiracetam index (SI) during NREM-sleep with baseline SI before initiation of LEV. The clinical efﬁcacy of LEV was

assessed by comparing seizure frequency at the end of follow up with the baseline. The follow up

duration varied from 18 to 53 months.

Results: Electrographic response was observed in 11 patients. Eight patients demonstrated a lasing

response (more than 12 months): ﬁve from symptomatic, two – cryptogenic and one – idiopathic group

respectively. Three children showed a partial response (6–12 months): one from symptomatic and two

from idiopathic group.

Eleven out of the 20 children were seizure free at baseline and during the whole follow up. The rest,

six-symptomatic and three-cryptogenic patients, had seizures prior to LEV treatment initiation. Six

became seizure free after add-on therapy with LEV, and in three children a signiﬁcant reduction of

seizure frequency was observed.

Conclusion: This study suggests that add-on therapy with LEV is more effective in children with CSWS

resulting from a known underlying structural brain lesion (the symptomatic group).

1. Introduction clinical impairment observed in these children. The presence of

CSWS on the EEG is almost certainly enough for the appearance of

Epileptic syndromes with continuous spikes-waves during cognitive impairments. Evidence suggests that suppression of this

sleep represent a wide spectrum of epileptic conditions which have epileptic activity can quite dramatically improve these func-

2,3

CSWS as a common speciﬁc EEG-feature. These conditions are of tions.

variable severity, duration and outcome. During the period when Successful treatment of epileptic syndromes with CSWS has

spike-wave activity during sleep dominates the EEG record, a always been problematic, usually offering little or no respite from

marked decrease in performance is usually observed, and can symptoms, or at best, a transitory response. The most commonly

include impairment of cognitive, language, motor or behavioural used drugs are sodium valproate, benzodiazepines, ethosuximide,

1 1,5–8

functions. sultiame and steroids. However there is no general agreement,

The mechanisms underlying these neuropsychological distur- whether steroids or antiepileptic drugs should be used as a ﬁrst

bances have yet to be clariﬁed. Many studies have attempted to choice medication, or on the duration of treatment after reaching

correlate the amount of spike-wave activity under sleep with the clinical and electrographic improvement. During recent years the

potential efﬁcacy of some new antiepileptic drugs, such as

lamotrigine, topiramate, and, especially, levetiracetam, has been

9–12

demonstrated in the treatment of CSWS. LEV is a water soluble

* Corresponding author. Tel.: +45 58 27 11 93; fax: +45 58 27 11 88.

pyrrolidine derivative and an analogue of piracetam. The efﬁcacy of

E-mail addresses: mdat@filadelfia.dk (M. Atkins), mnk@filadelfia.dk

LEV as an add-on medication in focal epilepsies has been well

(M. Nikanorova).

c documented. However, the mode of action of LEV is not

Tel.: +45 58 27 10 67; fax: +45 58 27 14 71.

636 M. Atkins, M. Nikanorova / Seizure 20 (2011) 635–639

completely understood. LEV may act by selectively preventing seizure frequency at the end of follow up with the baseline. The

hypersynchronisation of epileptiform burst ﬁring, thus inhibiting follow up period comprised 18–53 months.

the spread of spike activity. Recently the synaptic vesicle protein

SV2A, has been suggested as a possible binding site for LEV. A 2.1. Electrographic criteria for CSWS

beneﬁcial effect of LEV in epileptic syndromes with CSWS has been

11,12,16,17

reported by several investigators. However these reports The accepted morphology for epileptiform activity was a spike

have either evaluated a small number of children or followed them (duration between 20 and 70 ms) followed by a slow wave, with a

during a short period. frequency between 1 and 4 Hz. All children in the study had at least

We report on a larger prospective study carried out over a one recording where the percentage of epileptic discharges in

longer period of time; 20 children were evaluated during a period NREM-sleep exceeded 80%.

of 18–53 months.

2.2. Quantiﬁcation of epileptiform activity during sleep

2. Patients and methods

The percentage of epileptiform activity occurring during sleep

We studied 20 children (fourteen boys and six girls) aged can be expressed as the spike index (SI). The method of arriving at

between four and thirteen years with CSWS resulting from various the SI varies from centre to centre. In our centre we use a semi

aetiologies: six cases were idiopathic, seven – cryptogenic and automatic quantiﬁcation method based on spike-detection, using

seven – symptomatic. Age at CSWS detection varied from ﬁve to patient speciﬁc template matching. The percentage is calculated

ten years, CSWS duration – from ﬁve to 50 months (Table 1). In all using the sum of the periods of NREM-sleep during the whole

patients the efﬁcacy of the consecutive treatment with the night.

conventional AEDs (sodium valproate, benzodiazepines, ethosux- Electrographic data for each child was collected over a

imide, sultiame) was lacking in terms of EEG features and minimum period of 18 months, and for many patients, consider-

neuropsychological characteristics. Eleven out of 20 children were ably longer (Tables 2 and 3). The qualitative data (Table 2) included

seizure-free before LEV introduction. presence of background slowing on the EEG, the regional location

Before initiation of LEV therapy all patients underwent of the predominant spike-wave activity in wakefulness and sleep.

magnetic resonance imaging (MRI), 24-h EEG recording and The mode of distribution of spike-wave activity during sleep was

neuropsychological testing using Wechsler Intelligence Scale for considered either regional, deﬁned as consistently occurring over

Children III (WISC-III) and Wechsler Preschool and Primary Scale of one location/region without spread to the contra-lateral hemi-

Intelligence Revised (WPPSI-R). In 4 children the Leiter Interna- sphere, or focal with secondary bilateral synchrony (SBS), as

tional Performance Scale was used because of severe cognitive deﬁned by Blume and Pillay, and occurring over both hemi-

deterioration and lack of the ability to cooperate with verbal tasks. spheres.

The assessment of cognitive development was based on the full IQ The quantitative data (Table 3) included: the epilepsy

(intelligence quotient) scores: 80–100, normal, 60–80, mild delay, syndrome, the number of years with known CSWS, the baseline

50–60, moderate delay and <50, severe delay. spike-index (BSI)-deﬁned as the SI from the EEG control prior to the

LEV was administered as add-on therapy at the doses 45– start of LEV as add-on treatment, the number of months in LEV

50 mg/kg/day. All concomitant AEDs remained unchanged. The treatment (range 18–53 months) and the last spike-index (LSI).

clinical efﬁcacy of LEV treatment was evaluated by comparing the The difference between the BSI and the LSI was deﬁned as the

electrographic response to LEV add-on treatment, and was

Table 1 subsequently graded as follows:

Patient clinical characteristics.

Total number n = 20 Responders: (Grade I) reduction in SI >50%

Gender

Partial responders: (Grade II) reduction in SI between 25 and Male 14 50%.

Female 6

Non responders: (Grade III) reduction in SI <25% or an increase in

Age (years)

Range 4–13 SI.

Epilepsy syndrome diagnosis

aBECTs 6

Epilepsy with CSWS 7

The electrographic response was also categorised in terms of its

Symptomatic focal epilepsy 7

duration. Absence of CSWS on the EEG for more than 12 months

CSWS aetiology

Idiopathic 6 was assessed as lasting response, for 6–12 months – as partial

Cryptogenic 7 response.

Symptomatic: 7

The number of patients was considered too small for statistical

Hypoxic–ischemic encephalopathy 3

analysis.

Focal polymicrogyria 2

Partial trisomy 13/21 1

Age at CSWS onset (years) 3. Results

Range 5–10

CSWS duration (months)

3.1. Clinical response

Range 5–50 a

Concomitant AEDs

VPA 4 Eleven from 20 children were seizure-free before initiation of

STM 5

LEV therapy and during whole follow up. Six patients from

VPA + CLB 3

symptomatic and three from cryptogenic group had seizures

VPA + STM 2

before LEV introduction. At the end of follow up six out of these

STM + CLB 4

STM + LTG 1 nine children were seizure-free (three symptomatic, three

VPA + ESM 1 cryptogenic), and signiﬁcant reduction of seizure frequency was

a TM observed in the remaining three patients. LEV was well tolerated

VPAL: valproate; S : sultiame; CLB: clobazam; LTG: lamotrigine; ESM:

ethosuximide. by all the patients.

M. Atkins, M. Nikanorova / Seizure 20 (2011) 635–639 637

Table 2

Electrographic characteristics: qualitative and response grade.

Patient Aetiology Background Predominant paroxysmal Predominant paroxysmal Apparent SBS

number slowing abnormality – awake abnormality – asleep or regional

1 Cryptogenic No Right F+pT (R) pT+F Regional

2 Cryptogenic No F/T F->T SBS

3 Cryptogenic No F/P F SBS

4 Cryptogenic Yes F/T F->T SBS

5 Cryptogenic No Right F/T (R) F->T SBS in periods

6 Cryptogenic No Left T (L) T SBS in periods

7 Cryptogenic No Left P/T+F (L) P+F->C SBS

8 Symptomatic No Left F/T F->T SBS

9 Symptomatic Yes Left F/T F SBS

10 Symptomatic No Left P/C/T (L) P/C/T Regional

11 Symptomatic No Left T/C (L) T/C Regional

12 Symptomatic No Right P/C (R) P/C Regional

13 Symptomatic No Right T/P (R) T SBS in periods

14 Symptomatic Yes Right T/P (R) T/P Regional

15 aBECTs No Right C/T/P (R) C/T Regional

16 aBECTs Yes Right P/C + Right F/T (R) P/C SBS in periods

(R) F/T

17 aBECTs No Right F/T + Right T/C/P (R) F->T SBS

(R) P/T

18 aBECTs Yes Right T/C (R) T/C Regional

19 aBECTs Yes Right P/T/C + Left P/T/C (R) P/T/C Regional

(L) P/T/C

20 aBECTs No Right T/C/P (R) T/C/P Regional

Later F Later F Later SBS

F: frontal; T: temporal; pT: post temporal; C: central; P: parietal.

3.2. Electrographic response medication. Patient 14 had two foci, one temporal, which in

periods triggered SBS, but responded well to LEV medication.

EEG response is summarized in Table 3. During NREM sleep, In the idiopathic group three patients did not develop SBS.

discharges usually show a fronto-central or fronto-temporal These patients did not usually exhibit frontal spike-waves, but

maximum. The general trend in our population with cryptogenic tended to show a maximum in the centro-temporo-parietal

aetiology was a frontal maximum, sometimes with temporal regions. Patient 15 responded well to LEV treatment and patient

spreading and SBS, and they did rather badly on medication. The 18 showed a partial response. Patient 16 had two foci, the frontal

exceptions were patients one and ﬁve, one of whom had regional focus being the less dominant and occasionally triggering SBS. This

spike-waves over the frontal and post temporal region, with patient also showed a partial response to LEV treatment.

accentuation of the post temporal discharges during sleep, and no Thus, in cryptogenic group (patients one to seven), two patients

SBS. This patient responded well to LEV treatment. Another had showed a lasting response, and the remaining ﬁve – no response. In

frontal spike-waves and occasional SBS, and also responded well to symptomatic group (patients 8–14), all but one, showed improve-

LEV treatment. ment: ﬁve – lasting response and one – partial response. In

The symptomatic group had the least tendency to SBS and idiopathic group (patients 15–20), a lasting response was

generally responded well to LEV treatment. Patients eight and nine demonstrated only in one child. Two children showed a partial

had frontal spike-waves and SBS, but responded well to LEV response and in three no improvement was observed.

Table 3

Electrographic characteristics: quantitative and response grade.

Pt Age, years Gender Aetiology BSI Months in LEV treatment LSI Response grade

1 10 F Crypt. 48 41 No CSWS I

2 5 F Crypt. Not known 53 95 III

3 8 M Crypt. 70 33 64 III

4 6 M Crypt. 87 47 97. III

5 12 M Crypt. 48 30 No CSWS I

6 6 M Crypt. 65 18 88 III

7 4 M Crypt. 85 18 76 III

8 12 M Sympt. 80 18 Norm I

9 13 F Sympt. 65 43 No CSWS I

10 9 M Sympt. 80 26 55 II

11 9 M Sympt. 86 30 40 I

12 10 F Sympt. 86 18 No CSWS I

13 11 M Sympt. 54 45 67 III

14 11 F Sympt. 52 25 Norm I

15 7 M Idiopat. 80 19 No CSWS I

16 9 F Idiopat. 87 24 56 II

17 7 M Idiopat. 75 32 89 III

18 4 M Idiopat. 82 27 60 II

19 6 M Idiopat. 46 25 46 III

20 5 M Idiopat. Not known 23 80 III

BSI: baseline spike-wave index; LSI: last spike-wave index. Response grade as described under Section 2.

638 M. Atkins, M. Nikanorova / Seizure 20 (2011) 635–639

Table 4

between the epileptic discharges during sleep and the deteriora-

Cognitive development before and after LEV therapy.

tion of cognitive and behavioural functions is generally accept-

22,23

Groups of patients/cognitive development Before LEV At the end of ed, even though the mechanisms underlying these

therapy follow-up

disturbances remain unclear. At this present time, the goal of

Idiopathic (n = 6) treatment must be the effective reduction of epileptic discharges

Normal 4 1 during sleep over as long a period as possible, if not permanently.

Mild delay 1 4

Some of the problems experienced in reporting on the apparent

Moderate delay 1 1

efﬁcacy of a chosen medication in the treatment of CSWS include

Severe delay 0 0

spontaneous recovery in some patients, transient electrographic

Cryptogenic (n = 7)

Normal 2 0 and clinical changes that are not related to alterations in

Mild delay 3 2

medication, and the unpredictability of relapse. We have tried

Moderate delay 1 2

to overcome these problems by evaluating children over a longer

Severe delay 1 3

period and using ﬁxed methods of quantitative and qualitative

Symptomatic (n = 7)

Normal 1 1 evaluation, at a maximum of 6 monthly intervals. Concomitant

Mild delay 2 1 medications remained unchanged during the study.

Moderate delay 1 1

Whilst the three epileptic syndrome groups share many similar

Severe delay 3 4

clinical and electrographic manifestations during sleep, the

response to LEV appears to differ between these groups, showing

increased efﬁcacy in the symptomatic group, as was also shown by

3.3. Neuropsychological outcome Capovilla et al.

We cannot at this time explain why this should be so, or indeed,

Before the initiation of LEV therapy four out of six patients in whether it is only a chance ﬁnding.

the idiopathic group had normal cognitive development, one child We considered the presence of SBS, which by deﬁnition

– mild and one – moderate delay. In the cryptogenic group two out suggests a cortical site of hyperexcitability in the leading

of seven children had normal IQ scores, three – mild delay, one – hemisphere, capable of rapid transverse of the corpus callosum.

moderate and one – severe delay in the cognitive development. In Experimental data has shown that, the burst ﬁring pattern

the symptomatic group one patient out of seven had initially associated with spindling in the early sleep stages can develop

normal cognitive development, two were mildly delayed, two – into bilateral synchronous self sustaining spike-wave discharges.

moderately and three – severely delayed. The neuropsychological Furthermore, this phenomenon may be age limited. Related to

outcome is presented in Table 4. In both idiopathic and cryptogenic the purpose of our study, we found that children not exhibiting SBS

groups the cognitive development declined, despite the clinical seemed to respond better to LEV treatment.

and electrographical improvement. However in symptomatic Secondly, we considered the location of the predominant

group no signiﬁcant neuropsychological deterioration was ob- paroxysmal activity. As reported by Blume and Pillay, SBS favours

served at the end of follow-up. The duration of CSWS was the main a frontal location – this was a trend we found. The temporal and

predictor of the severity of neuropsychological outcome showing a parietal paroxysmal locations correlated generally with a better

linear correlation: the longer was the duration of CSWS, the poorer response to LEV treatment.

was the outcome. This data is in accordance with the other 1,20,21

studies. 5. Conclusion

4. Discussion LEV as an add-on treatment 45–50/mg/kg/day, would seem to

be an effective and lasting treatment for children with CSWS

This is the ﬁrst study showing LEV, as add-on therapy, to be resulting from symptomatic epilepsy, where the paroxysmal

effective over a long period of time in children with CSWS activity has a regional location without SBS. In the future, further

resulting from symptomatic epilepsy. Moreover, this study evaluation using a larger population is required. Additionally, the

reveals only partial or no effect in the majority of cases with mechanisms triggering SBS, and their relevance to the spread of

CSWS of other aetiologies, namely idiopathic or the classic CSWS epileptic discharges in the CSWS-syndrome require further

syndrome. evaluation.

A limited number of previous studies have shown LEV to be

effective in CSWS resulting from various aetiologies. Kramer Conﬂict of interest

et al. reported efﬁcacy in seven of 17 children, the duration

and relapse rate unknown. Wang et al. demonstrated LEV None.

efficacy in five of six children, but two of five responders

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